Biotechnology’s advance presents dark possibilities. Terrorists can develop biological weapons. Worse, the life sciences could give malefactors the ability to manipulate fundamental life processes—and even affect human behavior. The Knowledge By Mark Williams

44 FEATURE STORY TECHNOLOGY REVIEW march /april 2006 ast year, a likable and accomplished scientist named Serguei In 1973, Soviet bioweaponeer Popov, who for nearly two decades developed genetically Serguei Popov was a student in engineered biological weapons for the , crossed Novosibirsk, . the Potomac River to speak at a conference on bioterrorism in Washington, DC. L Popov, now a professor at the National Center for and Infec- tious Diseases at , is tallish, with peaked eye- brows and Slavic cheekbones, and, at 55, has hair somewhere between sandy and faded ginger. He has an open, lucid gaze, and he is courteously soft-spoken. His career has been unusual by any standards. As a student in his native city of Novosibirsk, Siberia’s capital, preparing his thesis on DNA synthesis, he read the latest English-language publications on the new molecular biology. After submitting his doctorate in 1976, he joined , the Soviet pharmaceutical agency that secretly developed bio- logical weapons. There, he rose to become a department head in a com- prehensive program to genetically engineer biological weapons. When the program was founded in the 1970s, its goal was to enhance classical agents of for heightened pathogenicity and resistance to antibiotics; by the 1980s, it was creating new species of designer patho- gens that would induce entirely novel symptoms in their victims. In 1979, Popov spent six months in Cambridge, England, studying the technologies of automated DNA sequencing and synthesis that were emerg- ing in the West. That English visit, Popov recently told me, needed some arranging: “I possessed state secrets, so I could not travel abroad without a special decision of the Central Committee of the Communist Party. A special legend, essentially, that I was an ordinary scientist, was developed for me.” The cover “legend” Popov’s superiors provided proved useful in 1992, after the U.S.S.R. fell. When the Russian state stopped paying sala- ries, among those a� ected were the 30,000 scientists of Biopreparat. Broke, with a family to feed, Popov contacted his British friends, who arranged funding from the Royal Society, so he could do research in the United Kingdom. The KGB (whose control was in any case limited by then) let him leave Russia. Popov never returned. In England, he studied HIV for six months. In 1993, he moved to the University of Texas Southwestern Medical Center, whence he sent money so that his wife and children could join him. He remained in Texas until 2000, attracting little interest. “When I came to Texas, I decided to forget everything,” Popov told me. “For seven years I did that. Now it’s di� erent. It’s not because I like talking about it. But I see every day in publications that nobody knows what was done in the Soviet Union and how important that work was.” Yet if Popov’s appearance last year at the Washington conference is any indication, it will be di� cult to convince policymakers and scientists of the relevance of the Soviet bioweaponeers’ achievements. It wasn’t only that Popov’s audience in the high-ceilinged chamber of a Senate o� ce building found the Soviets’ ingenious applications of biological science morally repugnant and technically abstruse. Rather, what Popov said lay COU RTESY OF SE RG U E I POPOV I E U RG SE OF RTESY COU Editor’s note: Conscious of the controversial nature of this article, Technol- ogy Review asked Allison Macfarlane, a senior research associate in the Tech- nology Group of MIT’s Security Studies Program, to rebut its argument: see “Assessing the Threat,” page 34. We were also careful to elide any recipes for developing a biological weapon. Such details as do appear have been published before, mainly in scientifi c journals.

TECHNOLOGY REVIEW march /april 2006 FEATURE STORY 45 so far outside current arguments about biodefense that he “Sooner or later, it is reasonable to expect the appearance sounded as if he had come from another planet. of ‘bio-hackers.’” The conference’s other speakers focused on the boom in Malefactors would have more trouble stealing or buy- U.S. biodefense spending since the attacks of September 11, ing the classical agents of biological warfare than synthe- 2001, and the scare that same year. The bacteriologist sizing new ones. In 2002, after all, a group of researchers Richard Ebright, a professor of chemistry and chemical biol- built a functioning polio virus, using a genetic sequence ogy at Rutgers University, fretted that the enormous increase o� the Internet and mail-order oligonucleotides (machine- in grants to study three of the category A bacterial agents synthesized DNA molecules no longer than about 140 bases (that is, anthrax, plague, and ) drained money from each) from commercial synthesis companies. At the time, the basic research to � ght existing epidemics. Ebright (who’d group leader, Eckard Wimmer of the State University of New persuaded 758 other scientists to sign a letter of protest to York at Stony Brook, warned that the technology to synthe- Elias Zerhouni, the director of the National Institutes of size the much larger genome of variola major—that is, the Health) also charged that by promiscuously dissemi nating deadly virus—would come within 15 years. In fact, bioweaponeering knowledge and pathogen specimens to it arrived sooner: December 2004, with the announcement newly minted biodefense labs around the United States, “the of a high-throughput DNA synthesizer that could reproduce NIH was funding a research and development arm of al- smallpox’s 186,000-odd bases in 13 runs. Qaeda.” Another speaker, Milton Leitenberg, introduced as The possibility of terrorists’ gaining access to such one of the grand old men of weapons control, was more high-end technology is worrisome. But few have pub- splenetic. The current obsession with bioterrorism, the rum- licly stated that engineering certain types of recombinant pled, grandfatherly Leitenberg insisted, was nonsense; the microörganisms using older equipment—nowadays cheaply record showed that almost all bioweaponeering had been available from eBay and online marketplaces for scienti� c done by state governments and militaries. equipment like LabX—is already feasible.feasible. TheThe biomedicalbiomedical Such arguments are not without merit. So why do Serguei community’s reaction to all this has been a general � inching. Popov’s accounts of what the Russians assayed in the eso- (The signatories to the National Academies report are an teric realm of genetically engineered bioweapons, using pre- exception.) Caution, denial, and a lack of knowledge about genomic biotech, matter now? bioweaponeering seem to be in equal parts responsible. Jens They matter because the Russians’ achievements tell us Kuhn, a virologist at Harvard Medical School, told me, “The what is possible. At least some of what the Soviet bioweap- Russians did a lot in their bioweapons program. But most of oneers did with di� culty and expense can now be done that isn’t published, so we don’t know what ttheyhey kknow.”now.” easily and cheaply. And all ofof wwhathat ttheyhey aaccomplishedccomplished ccanan bbee On a winter’s afternoon last year, in the hope of discover- duplicated with time and money. We live in a world where ing just what the Russians had done, I set out along Highway gene-sequencing equipment bought secondhand on eBay and 15 in Virginia to visit Serguei Popov at the Manassas campus unregulated biological material delivered in a FedEx package of George Mason University. Popov came to the National provide the means to create biological weapons. Center for Biodefense after buying a book called Biohazard in 2000. This was the autobiography of Ken Alibek, Biopre- Build or Buy? parat’s former deputy chief, its leading scientist, and Pop- There is growing scienti� c consensus that biotechnology— ov’s ultimate superior. One of its passages described how, in especially, the technology to synthesize ever larger DNA 1989, Alibek and other Soviet bosses had attended a presen- sequences—has advanced to the point that terrorists and tation by an unnamed “young scientist” from Biopreparat’s rogue states could engineer dangerous novel pathogens. bacterial-research complex at Obolensk, south of . In February, a report by the Institute of Medicine and Following this presentation, Alibek wrote, “the room was National Research Council of the National Academies enti- absolutely silent. We all recognized the implications of what tled “Globalization, Biosecurity, and the Future of the Life the scientist had achieved. A new class of weapons had been Sciences” argued, “In the future, genetic engineering and found. For the � rst time, we would be capable of producing other technologies may lead to the development of patho- weapons based on chemical substances produced naturally genic organisms with unique, unpredictable characteristics.” by the human body. They could damage the nervous system, Pondering the possibility of these recombinant pathogens, alter moods, trigger psychological changes, and even kill.” the authors note, “It is not at all unreasonable to anticipate When Popov read that, I asked him, had he recognized that [these] biological threats will be increasingly sought the “young scientist?” “Yes,” he replied. “That was me.” after…and used for warfare, terrorism, and criminal pur- After reading Biohazard, PPopovopov ccontactedontacted AAlibeklibek aandnd ttoldold poses, and by increasingly less sophisticated and resourced him that he, too, had reached America. Popov moved to Vir- individuals, groups, or nations.” The report concludes, ginia to work for Alibek’s company, Advanced Biosystems,

46 FEATURE STORY TECHNOLOGY REVIEW march /april 2006 and was debriefed by U.S. intelligence. In 2004 he took up picture: an industrial program that consumed tons of chemi- his current position at the National Center for Biodefense, cals and marshalled large numbers of biologists to construct, where Alibek is a distinguished professor. over months, a few hundred bases of a gene that coded for Regarding the progress of biotechnology, Popov told me, a single protein. “It seems to most people like something that happens in Though some dismiss Biopreparat’s pioneering e� orts a few places, a few biological labs. Yet now it is becoming because the Russians relied on technology that is now anti- widespread knowledge.” Furthermore, he stressed, it is quated, this is what makes them a good guide to what could knowledge that is Janus-faced in its potential applications. be done today with cheap, widely available biotechnology. “When I prepare my lectures on genetic engineering, what- Splicing into pathogens synthesized mammalian genes cod- ever I open, I see the possibilities to make harm or to use ing for the short chains of amino acids called peptides (that the same things for good—to make a biological weapon or is, genes just a few hundred bases long) was handily within to create a treatment against disease.” reach of Biopreparat’s DNA synthesis capabilities. E� orts on The “new class of weapons” that Alibek describes Pop- this scale are easily reproducible with today’s tools. ov’s creating in Biohazard iiss a ccasease inin ppoint.oint. IIntonto a rrelativelyelatively innocuous bacterium responsible for a low-mortality pneu- What the Russians Did monia, Legionella pneumophila, Popov and his researchers The Soviet bioweapons program was vast and labyrinthine; spliced mammalian DNA that expressed fragments of myelin not even Ken Alibek, its top scienti� c manager, knew every- protein, the electrically insulating fatty layer that sheathes thing. In assessing the extent of its accomplishment—and our neurons. In test animals, the pneumonia infection came thus the danger posed by small groups armed with modern and went, but the myelin fragments borne by the recombi- technology—we are to some degree dependent on Serguei nant Legionella goaded the animals’ immune systems to Popov’s version of things. Since his claims are so controver- The Russians’ achievements tell us what is possible. At least some of what the Soviet bioweaponeers did with difficulty and expense can now be done easily and cheaply. And all of what they accomplished can be duplicated with time and money. read their own natural myelin as pathogenic and to attack sial, a question must be answered: Many (perhaps most) it. Brain damage, paralysis, and nearly 100 percent mortality people would prefer to believe that Popov is lying. Is he? resulted: Popov had created a biological weapon that in e� ect Popov’s a� liation with Alibek is a strike against him at triggered rapid multiple sclerosis. (Popov’s claims can be cor- the U.S. Army Medical Research Institute of Infectious Dis- roborated: in recent years, scientists researching treatments eases (Usamriid) at Fort Detrick, MD, where Biopreparat’s for MS have employed similar methods on test animals with former top scientist has his critics. Alibek, one knowledge- similar results.) able person told me, e� ectively “entered the storytelling busi- When I asked about the prospects for creating bioweapons ness when he came to America.” Alibek’s critics charge that through synthetic biology, Popov mentioned the polio virus because he received consulting fees while brie� ng U.S. sci- synthesized in 2002. “Very prominent people like [Anthony] entists and o� cials, he exaggerated Soviet bioweaponeering Fauci at the NIH said, ‘Now we know it can be done.’” Popov achievements. In particular, some critics reject Alibek’s claims paused. “You know, that’s…naïve. In 1981, I described how that the U.S.S.R. had combined Ebola and other viruses—in to carry out a project to synthesize small but biologically order to create what Alibek calls “chimeras.” The necessary active viruses. Nobody at Biopreparat had even a little doubt technology, they insist, didn’t yet exist. When I interviewed it could be done. We had no DNA synthesizers then. I had 50 Alibek in 2003, however, he was adamant that Biopreparat people doing DNA synthesis manually, step by step. One step had wweaponizedeaponized EEbola.bola. was about three hours, where today, with the synthesizer, Alibek and Popov obviously have an interest in talking up it could be a few minutes—it could be less than a minute. Russia’s bioweapons. But neither I, nor others with whom Nevertheless, already the idea was that we would produce I’ve compared notes, have ever caught Popov in a false state- one virus a month.” ment. One must listen to him carefully, however. Regarding E� ectively, Popov said, Biopreparat had few restrictions Ebola chimeras, he told me when I � rst interviewed him in on manpower. “If you wanted a hundred people involved, it 2003, “You can speculate about a plague-Ebola combination. was a hundred. If a thousand, a thousand.” It is a startling I know that those who ran the Soviet bioweapons program

TECHNOLOGY REVIEW march /april 2006 FEATURE STORY 47 studied that possibility. I can talk with certainty about a synthesis of plague and Venezuelan equine encephalitis, because I knew the guy who did that.” Popov then described a Soviet strategy for hiding deadly viral genes inside some milder bacterium’s genome, so that medical treatment of a victim’s initial symptoms from one microbe would trigger a second microbe’s growth. “The � rst symptom could be plague, and a victim’s fever would get treated with something as simple as tetracycline. That tetracycline would itself be the factor inducing expression of a second set of genes, which could be a whole virus or a com- bination of viral genes.” In short, Popov indicated that a plague-Ebola combination was theoretically possible and that Soviet scientists had studied that possi bility. Next, he made another turn of the screw: Bio- preparat had researched recombinants that would e� ectively turn their victims into walk- ing Ebola bombs. I had asked Popov for a pic- ture of some worst-case scenarios, so I cannot complain that he was misleading me—but the Russians almost certainly never created the plague-Ebola combination. One further testimonial to Popov: the man himself is all of a piece. Recalling his youth in Siberia, he told me, “I believed in the future, the whole idea of socialism, equity, and social jus- tice. I was deeply afraid of the United States, the aggressive Access codes were stamped on Serguei Popov’s Biopreparat ID. American military, capitalism—all that was deeply scary.” He added, “It’s di� cult to communicate how people in the logical weapons,” he told me. “Simply, it was supposed to be Soviet Union thought then about themselves and how much peaceful research, which would transition from pure science excitement we young people had about science.” Biological- to a new microbiological industry.” Matters proceeded, how- weapons development was a profession into which Popov ever. “Your boss says, ‘We’d like you to join a very interest- was recruited in his 20s and which informed his life and ing project.’ If you say no, that’s the end of your career. Since thinking for years. To ask him questions about biological I was ambitious then, I went further and further. Initially, I weapons is to elicit a cascade of analysis of the speci� c cell- had a dozen people working under me. But the next year I signaling pathways and receptors that could be targeted to got the whole department of � fty people.” induce particular e� ects, and how that targeting might be In 1979, Popov received orders to start research in achieved via the genetic manipulation of pathogens. Popov which small, synthesized genes coding for production of is not explicable unless he is what he claims to be. beta-endorphins—the opioid neurotransmitters produced in Popov’s research in Russia is powerfully suggestive of the response to pain, exercise, and other stress—were to be spliced strangeness of recombinant biological weapons. Because into viruses. Ostensibly, this work aimed to enhance the patho- genetics and molecular biology were banned as “bourgeois gens’ virulence. Popov shrugged, recalling this. “How could science” in the U.S.S.R. until the early 1960s, Popov was we increase virulence with endorphins? Still, if some general among the � rst generation of Soviet university graduates to tells you, you do it.” Popov noted that the particular general POPOV I E U RG SE OF RTESY COU grow up with the new biology. When he � rst joined Vector, who ordered the project, Igor Ashmarin, was also a molecular or the State Research Center of Virology and Biotechnology, biologist and, later, an academician on Moscow State Univer- Biopreparat’s premier viral research facility near Novosi- sity’s biology faculty. “Ashmarin’s project sounded unrealis- birsk, he didn’t immediately understand that he had entered tic but not impossible. The peptides he suggested were short, the bioweaponeering business. “Nobody talked about bio- and we knew how to synthesize the DNA.”

48 FEATURE STORY TECHNOLOGY REVIEW march /april 2006 Peptides, such as beta-endorphins, are the constituent potentially a paci� cation agent. For more complex chemicals, parts of proteins and are no longer than 50 amino acids. you’d need the whole biological pathways that produce them. Nature exploits their compactness in contexts where cell Constructing those would be enormously di� cult. But any signaling takes place often and rapidly—for instance, in the drug stimulates speci� c receptors, and that is doable in dif- central nervous system, where peptides serve as neurotrans- ferent ways. So instead of producing the drug, you induce the mitters. With 10 to 20 times fewer amino acids than an consequences. Pathogens could do that, in principle.” average protein, peptides are produced by correspondingly Psychotropic recombinant pathogens may sound science smaller DNA sequences, which made them good candidates � ctional, but sober biologists support Popov’s analysis. Har- for synthesis using Biopreparat’s limited means. Popov set vard University professor of molecular biology Matthew a research team to splicing synthetic endorphin-expressing Meselson is, with Frank Stahl, responsible for the historic genes into various viruses, then infecting test animals. Meselson-Stahl experiment of 1957, which proved that DNA Yet the animals were una� ected. “We had huge pressure replicated semiconservatively, as Watson and Crick had to produce these more lethal weapons,” Popov said. “I was proposed. Meselson has devoted much e� ort to preventing in charge of new projects. Often, it was my responsibility biological and chemical weapons. In 2001, warning that to develop the project, and if I couldn’t, that would be my biotechnology’s advance was transforming the possibilities problem. I couldn’t say, ‘No, I won’t do it.’ Because, then, what of bioweaponeering, he wrote in the New York Review of about your children? What about your family?” To appease Books, “As our ability to modify life processes continues its their military bosses, Popov and his researchers shifted to rapid advance, we will not only be able to devise additional peptides other than beta-endorphins and discovered that, ways to destroy life but will also become able to manipulate indeed, microbes bearing genes that expressed myelin pro- it—including the fundamental biological processes of cogni- tein could provoke animals’ immune systems to attack their tion, development, reproduction, and inheritance.” own nervous systems. While the Vector team used this tech- I asked Meselson if he still stood by this. “Yes,” he said. nique to increase the virulence of vaccinia, with the ultimate After telling him of Popov’s accounts of Russian e� orts to goal of applying it to smallpox, Popov was sent to Obolensk engineer neuromodulating pathogens, I said I was dubious to develop the same approach with bacteria. Still, he told me, that biological weapons could achieve such speci� c e� ects. “We now know that if we’d continued the original approach “Why?” Meselson bluntly asked. He didn’t believe such with beta-endorphins, we would have seen their e� ect.” agents had been created yet—but—but ttheyhey wwereere possiblepossible.. This vision of subtle bioweapons that modi� ed behav- No one knows when such hypothetical weapons will ior by targeting the nervous system—inducing e� ects like be real. But since Popov left Russia, the range and power temporary schizophrenia, memory loss, heightened aggres- of biotechnological tools for manipulating genetic control sion, immobilizing depression, or fear—was irresisti bly circuits have grown. A burgeoning revolution in “targeting attractive to Biopreparat’s senior military scientists. After speci� city” (targeting is the process of engineering molecules Popov’s defection, the research continued. In 1993 and to recognize and bind to particular types of cells) is creating 1994, two papers, copublished in Russian science jour- new opportunities in pharmaceuticals; simultaneously, it is nals by Ashmarin and some of Popov’s former colleagues, advancing the prospects for chemical and biological weap- described experiments in which of recombinant ons. Current research is investigating agents that target the tularemia successfully produced beta-endorphins in test distinct biochemical pathways in the central nervous system animals and thereby increased their thresholds of pain sen- and that could render people sedate, calm, or otherwise sitivity. These apparently small claims amount to a proof of incapaci tated. All that targeting speci� city could, in princi- concept: bioweapons can be created that target the central ple, also be applied to biological weapons. nervous system, changing perception and behavior. The disturbing scope of the resulting possibilities was I asked Popov whether bioweaponeers could design alluded to by George Poste, former chief scientist at Smith- pathogens that induced the type of e� ects usually associ- Kline Beecham and the sometime chairman of a task force on ated with psychopharmaceuticals. bioterrorism at the U.S. Defense Department, in a speech he “Essentially, a pathogen is only a vehicle,” Popov replied. gave to the National Academies and the Center for Strategic “Those vehicles are available—a huge number of pathogens and International Studies in Washington, DC, in January you could use for di� erent jobs. If the drug is a peptide like 2003. According to the transcript of the speech, Poste recalled endorphin, that’s simple. If you’re talking about triggering the that at a recent biotech conference he had attended a presen- release of serotonin and dopamine—absolutely possible. To tation on agents that augment memory: “A series of aged rats cause amnesia, schizophrenia—yes, it’s theoretically possible were paraded with augmented memory functions…. And with pathogens. If you talk about paci� cation of a subject popu- some very elegant structural chemistry was placed onto the lation—yes, it’s possible. The beta-endorphin was proposed as board…. Then with the most casual wave of the hand the

TECHNOLOGY REVIEW march /april 2006 FEATURE STORY 49 presenter said, ‘Of course, modi� cation of the methyl group that his research team had developed a new high-throughput at C7 completely eliminates memory. Next slide, please.’” synthesizer capable of constructing in one pass a DNA mole- cule 14,500 bases long. Basement Biotech Church says his DNA synthesizer could make and The age of bioweaponeering is just dawning: almost all of pharmaceutical production vastly more e� cient. But it could the � eld’s potential development lies ahead. also enable the manufacture of the genomes of all the viruses The recent report by the National Academies described on the U.S. government’s “select agents” list of bioweapons . many unpleasant scenarios: in addition to psychotropic Church fears that starting with only the constituent chemical pathogens, the academicians imagine the misuse of “RNA reagents and the DNA sequence of one of the select agents, interference” to perturb gene expression, of nanotech nology someone with su� cient knowledge might construct a lethal to deliver toxins, and of viruses to deliver antibodies that virus. The smallpox virus variola, for instance, is approxi- could target ethnic groups. mately 186,000 bases long—just 13 smaller DNA mole cules to This last is by no means ridiculous. Microbiologist Mark be synthesized with Church’s technology and bound together Wheelis at the University of California, Davis, who works into one viral genome. To generate infectious particles, the with the Washington-based Center for Arms Control and synthetic variola would then need to be “booted” into opera- Non-Proliferation, notes in an article for Arms Control Today, tion in a host cell. None of this is trivial; nevertheless, with “Engineering an ethnic-speci� c weapon targeting humans the requisite knowledge, it could be done. is...di� cult, as human genetic variability is very high both I suggested to Church that someone with the requisite within and between ethnic groups...but there is no reason knowledge might not need his cutting-edge technology to to believe that it will not eventually be possible.” do harm. A secondhand machine could be purchased from But commentators have focused on speculative perils for a website like eBay or LabX.com for around $5,000. Alter- decades. While the threats they describe are plausible, dire natively, the components—mostly o� -the-shelf electronics “I was in charge of new projects. Often, it was my responsibility to develop the project, and if I couldn’t, that would be my problem. I couldn’t say, ‘No, I won’t do it.’ Because, then, what about your children? What about your family?”

forecasts have become a ritual—a way to avoid more imme- and plumbing—could be assembled with a little more e� ort diate problems. Already, in 2006, much could be done. for a similar cost. Construction of a DNA synthesizer in this Popov’s myelin autoimmunity weapon could be repli- fashion would be undetectable by intelligence agencies. cated by bioterrorists. It would be no easy feat: while the The older-generation machine would construct only oligo- technological requirements are relatively slight, the scienti� c nucleotides, which would then have to be stitched together knowledge required is considerable. At the very least, ter- to function as a complete gene, so only small genes could be rorists would have to employ a real scientist as well as lab synthesized. But small genes can be used to kill people. technicians trained to manage DNA synthesizers and tend “People have trouble maintaining the necessary ultrapure pathogens. They would also have to � nd some way to dis- approach even with commercial devices—but you de� nitely perse their pathogens. The Soviet Union “weaponized” bio- could do some things,” Church acknowledged. logical agents by transforming them into � ne aerosols that What things? Again, Serguei Popov’s experience at Bio- could be sprayed over large areas. This presents engineering preparat is instructive. In 1981, Popov was ordered by Lev problems of an industrial kind, possibly beyond the ability Sandakhchiev, Vector’s chief, to synthesize fragments of of any substate actor. But bioterrorists might be willing to smallpox. “I was against this project,” Popov told me. “I infect themselves and walk through crowded airports and thought it was an extremely blunt, stupid approach.” It train stations: their coughs and sni� es would be the bombs amounted to a pointlessly di� cult stunt, he explained, to of their tterrorerror ccampaign.ampaign. impress the Soviet military; when his researchers acquired Di� cult as it may still be, garage-lab bioengineering real smallpox samples in 1983, the program was suspended. is getting easier every year. In the vanguard of those who A closely related program that Popov had started, however, are calling attention to biotechnology’s potential for abuse continued after he departed Vector for Biopreparat’s Oblensk is George Church, Harvard Medical School Professor of facility in the mid-1980s. This project used the poxvirus vac- Genetics. It was Church who announced in December 2004 cinia, the relatively harmless relative of variola used as a vac-

50 FEATURE STORY TECHNOLOGY REVIEW march /april 2006 cine against smallpox. Not only was vaccinia—whose genome might be expressed in the “wrong” organ. But according is very similar to variola’s—a convenient experimental stand- to several virologists with knowledge of biological weap- in for smallpox, but its giant size (by viral standards) also ons, the result of splicing IL-4 intointo cchickenpoxhickenpox mmightight bbee ttoo made it a congenial candidate to carry extra genes. In short, suppress the immune response to the disease. According to it was a useful model for bioweapons. For at least a decade, these virologists, the e� ect would be similar to what hap- therefore, a team of Biopreparat scientists systematically pens to cancer patients when they catch chickenpox. They inserted into vaccinia a variety of genes that coded for cer- often die—even when treated with antiviral therapies. For tain toxins and for peptides that act as signaling mechanisms healthy children or adults, chickenpox is usually a super- in the immune system. Though Popov had directed that the � cial disease that mainly a� ects the skin; but depending on recombinant-vaccinia program should proceed through the the immunosuppressive state of an infected cancer patient, genes coding for immune system–modulating peptides, he chickenpox lesions can be slow to heal, and the viscera— left before the researchers � nished with the interleukin that is, the lungs, the liver, and the central nervous system— genes. But it would be surprising if the Vector researchers become progressively diseased. did not reach the gene for interleukin-4 (IL-4), an immune- Bioterrorists could create a varicella-IL-4 recombinantrecombinant system peptide that coaxes white blood cells to increase their virus more easily than they could acquire or manufacture production of antibodies and then releases them. the pathogens that top the select-agents list. IL-4 iiss oonene ooff There is some evidence that the Russians discovered the the standard genes used in medical research; a plasmid of e� ects of inserting the IL-4 gene into a poxvirus. Those human IL-4 couldcould bebe orderedordered fromfrom oneone ofof thethe DNADNA syn-syn- e� ects are deadly. In 2001, Ian Ramshaw and a team of thesis jobbing companies and delivered via FedEx for $350. virolo gists from the Australian National University in Can- If our hypothetical bioterrorists were worried about detec- berra spliced IL-4 intointo ectromelia,ectromelia, a mousepoxmousepox virus,virus, and tion, they might avoid the DNA synthesis companies alto- learned that the resulting recombinant mousepox trig- gether. Conveniently, without its junk DNA, IL-4 isis onlyonly gered massive overproduction of the IL-4 peptide. Even about 462 base pairs long. It’s possible to download IL-4’s the immune systems of mice vaccinated against mouse- genetic sequence from the Internet, use a basic synthesizer pox could not control the growth of the virus: a 60 percent to construct it in � ve segments, and then assemble those seg- mortality rate resulted. Other experiments have con� rmed ments “manually,” as Popov’s scientists did. The other prin- the lethality of the recombinant pathogen. The American cipal tools needed would be a centrifuge—like the $5,000 poxvirus expert Mark Buller, of Saint Louis University in DNA synthesizer, cheaply available via Internet sites—and a Missouri, engineered various versions of the recombinant, transfection kit, a small bottle � lled with reagent that costs one of which maintained the mousepox virus’s full viru- less than $200 and which would be necessary to introduce lence while generating excessive interleukin-4. All tthehe micemice the IL-4 genegene intointo cchickenpox.hickenpox. FFinally,inally, tthehe terroriststerrorists wouldwould infected with this recombinant died. The BBC reported also require an incubator and the media in which to grow that when asked about the Australian experiment, San- the resulting cells . The total costs, including the DNA syn- dakhchiev, Vector’s director, remarked, “Of course, this is thesizer: probably less than $10,000. not a surprise.” Because vaccinia is universally available, it is fortunate Be Afraid. But of What? that a vaccinia-IL-4 hybridhybrid wouldwould notnot bebe anan e�e� ectiveective biologi-biologi- In the public debate about how to defend ourselves against cal weapon: vaccinia has limited transmissibility between biological weapons, the advance of biotechnology has been humans. Still, there are other poxviruses that are transmis-transmis- little discussed. Instead, most biologists and security ana- sible. Smallpox, the most infamous, is nearly impossible lysts have debated the merits and shortcomings of Project for aspiring bioterrorists to acquire. But another, varicella- BioShield, the Bush administration’s $5.6 billion plan to zoster, or common chickenpox, is easily acquired and even protect the U.S. population from biological, chemical, radio- more infectious than smallpox. logical, or nuclear attack. After last year’s bioterrorism con- What would happen if bioterrorists spliced IL-4 iintonto ference in DC, I called on Richard Ebright, whose Rutgers chickenpox and released the hybrid into the general popu- laboratory researches transcription initiation (the � rst step lation? Perhaps nothing. Very often, the Soviet bioweap- in gene expression), to hear why he so opposes the biode- oneers successfully spliced new genes into pathogens, only fense boom (in its current form) and why he doesn’t worry to � nd that infected test animals showed no symptoms. about terrorists’ synthesizing biological weapons. One reason was that the genetically engineered microbes “There are now more than 300 U.S. institutions with were often “environmentally unstable”—that is, they did not access to live bioweapons agents and 16,500 individuals retain the added genes. Engineering recombinant pathogens approved to handle them,” Ebright told me. While all of can be ine� ective for other reasons, too: the foreign gene those people have undergone some form of background

TECHNOLOGY REVIEW march /april 2006 FEATURE STORY 51 check—to verify, for instance, that they aren’t named on a conventional select agents such as smallpox, anthrax, and terrorist watch list and aren’t illegal aliens—it’s also true, Ebola, less relevant. Still, he maintained, “a conventional Ebright noted, that “Mohammed Atta would have passed bioweapons agent can potentially be massively disruptive those tests without di� culty.” in economic costs, fear, panic, and casualties. The need to Furthermore, Ebright told me, at the time of our inter- go to the next level is outside the incentive structure of any view, 97 percent of the researchers receiving funds from the substate organization.” National Institute of Allergy and Infectious Diseases to study Even those who are intimately involved with biodefense bioweapon agents had never been funded for such work often support this view. For an insider’s perspective, I con- before. Few of them, therefore, had any prior experience tacted Jens Kuhn, the Harvard Medical School virologist. handling these pathogens; multiple incidents of accidental The German-born Kuhn has worked not only at Usamriid, release had occurred during the previous two years. and at the Centers for Disease Control in Atlanta, but also— Slipshod handling of bioweapons-level pathogens is scary uniquely for a Westerner—at Vector. enough, I conceded. But isn’t the proliferation of bioweap- Kuhn, like Ebright, is no fan of how the biodefense boom oneering expertise, I asked, more worrisome? After all, is unfolding. “When I was at Usamriid, it exempli� ed how what reliable means do we have of determining whether a biodefense facility should be,” he told me. “That’s why I’m somebody set out to be a molecular biologist with the aim worried—because the system worked, and the experts were of developing bioweapons? concentrated at the right places, Fort Detrick and the CDC. “That’s the most signi� cant concern,” Ebright agreed. Now this expertise gets diluted, which isn’t smart.” “If al-Qaeda wished to carry out a bioweapons attack in the Kuhn believes, nevertheless, that some kind of national U.S., their simplest means of acquiring access to the materi- biodefense program is needed. He just doesn’t think we are als and the knowledge would be to send individuals to train preparing for the right things. “Everybody makes this con- within programs involved in biodefense research.” Ebright nection with bioterrorism, anthrax attacks, and al-Qaeda. paused. “And today, every university and corporate press That’s completely wrong.” Kuhn recalled his time at Vec- o� ce is trumpeting its success in securing research fund- tor and that facility’s grand scale. “When you look at what ing as part of this biodefense expansion, describing exactly the Russians did, those kinds of huge state programs with what’s available and where.” billions of dollars � owing into very sophisticated research As for the threat of next-generation bioweapons agents, carried on over decades—they’re the problem. If nation- Ebright was dismissive: “To make an antibiotic-resistant states start a Manhattan Project to build the perfect biologi- bacterial strain is frighteningly straightforward, within reach cal weapon, we’re in deep shit.” of anyone with access to the material and knowledge of how But doesn’t modern biotechnology, I asked, allow small to grow it.” However, he continued, further engineering— groups to do unprecedented things in garage laboratories? to increase virulence, to provide escape from vaccines, to Kuhn conceded, “There are a few things out there” with increase environmental stability—requires considerable skill the potential to kill people. But weighing the probabilities, he and a far greater investment of e� ort and time. “It’s clearly saw the threat in these terms: “De� nitely more biowarfare possible to engineer next-generation enhanced pathogens, than bioterrorism. De� nitely more the sophisticated bioweap- as the former Soviet Union did. That there’s been no bio- ons coming in the future than the stu� now. There’s dan- weapons attack in the United States except for the 2001 ger coming towards us and we’re focusing on concerns like anthrax attacks—which bore the earmarks of a U.S. bio- BioShield. I don’t think that’s the stu� that will save us.” defense community insider—means ipso facto thatthat no sub- state adversary of the U.S. has access to the basic means of Is Help on the Way? carrying it out. If al-Qaeda had biological weapons, they The 21st century will see a biological revolution analogous to would release them.” the industrial revolution of the 19th. But both its bene� ts and Milton Leitenberg, the arms control specialist, goes a step its threats will be more profound and more disruptive. further: he says because substate groups have not used bio- The near-term threat is that genes could be hacked out- logical weapons in the past, they are unlikely to do so in the side of large laboratories. This means that terrorists could near future. Such arguments are common in security circles. create recombinant biological weapons. But the leading Yet for many contemplating the onrush of the life sciences edge of bioweapon research has always been the work of and biotechnology, they have limited persuasiveness. government labs. The longer-term threat is what it always I suggested to Ebright that synthetic biology o� ered low- has been: national militaries. Biotechnology will furnish hanging fruit for a knowledgeable bioterrorist. He granted them wwithith wweaponseapons ooff uunprecedentednprecedented ppowerower aandnd sspeci�peci� cc-- that there were scenarios with sinister potential. He allowed ity. George Poste, in his 2003 speech to the National Acad- that biotechnology could make BioShield, which focuses on emies, warned his audience that in coming decades the life

52 FEATURE STORY TECHNOLOGY REVIEW march /april 2006 sciences would loom ever larger in national-security matters More immediately, no one has a good idea about what and international a� airs. Poste noted, “If you actually look should be done. Some scientists hope to arrest the spread at the history of the assimilation of technological advance of bioweapons knowledge. Rutgers’s Richard Ebright into the calculus of military a� airs, you cannot � nd a his- wants to reverse what he believes to be counterproductive torical precedent in which dramatic new technologies that in the funding of biodefense. More dramatically, Harvard’s redress military inferiority are not deployed.” George Church is calling for all DNA synthesizers to be Harvard’s Matthew Meselson has said the same and added registered internationally. “This wouldn’t be like regulat- that a world in which the new biotechnology was deployed ing guns, where you just give people a license and let them militarily “would be a world in which the very nature of con- do whatever they want,” he says. “Along with the license � ict had radically changed. Therein could lie unprecedented would come responsibilities for reporting.” Furthermore, opportunities for violence, coercion, repression, or subjuga- Church believes that just as all DNA synthesizers should tion.” Meselson adds, “Governments might have the objec- be registered, so should any molecular biologists research- ing the select agents or the human immune sys- tem response to pathogens. “Nobody’s forced to do research in those areas. If someone does, then they should be willing to have a very transparent, spotlighted research career,” Church says. But enactment of Church’s proposals would repre- sent an unprecedented regulation of science. Worse, not all nations would comply. For instance, Russian biologists, some of whom are known to have worked at Biopreparat, have reportedly trained molecular- biology students at the Pasteur Institute in Tehran. More fundamentally, arresting the progress of biological-weapons research is probably impracti- cal. Biological knowledge is all one, and therapies cannot be easily distinguished from weapons. For example, a general trend in biomedicine is to use viral vectors in gene therapy. Robert Carlson, senior scientist in the Genomation Lab and the Microscale Life Sciences Center in the Department of Electrical Engineering at the Univer- sity of Washington, believes there are two options. On the one hand, we can clamp down on biodefense research, stunting our ability to respond to biological threats. Alternatively, we can continue to push the boundaries of what is known about how pathogens In 1987, Biopreparat conducted a “pathogens class” at its research can be manipulated—spreading expertise in building biologi- complex in Obolensk. Serguei Popov is in the back row, far right. cal systems, for better and for worse, through experiments like Buller’s assembly of a mousepox-IL4 recombinant—sorecombinant—so tive of controlling very large numbers of people. If you have a we are not at a mortal disadvantage. One day, we must hope, situation of permanent con� ict, people begin contemplating technology will suggest an answer. things that the ordinary rules of con� ict don’t allow. They Serguei Popov has lived with these questions longer than begin to view the enemy as subhuman. Eventually, this leads most. When I asked him what could be done, he told me, to viewing people in your own culture as tools.” “I don’t know what kind of behavior or scienti� c or political What measures could mitigate both the near and the measures would guarantee that the new biology won’t hurt more distant threats of bioweaponry? BioShield, as it is now us.” But the vital � rst step, Popov said, was for scientists to constituted, will not protect us from genetically engineered overcome their reluctance to discuss biological weapons. pathogens. A number of radical solutions (like somehow “Public awareness is very important. I can’t say it’s a solu- boosting the human immune system through generic immu- tion to this problem. Frankly, I don’t see any solution right nomodi� ers) have been proposed, but even if pursued, they now. Yet � rst we have to be aware.”

COURTESY OF SERGUEI POPOV might take years or decades to develop. Mark Williams is a contributing writer to Technology Review.

TECHNOLOGY REVIEW march /april 2006 FEATURE STORY 53